Serum total homocysteine (tHcy) has been implicated in promoting venous thromboembolic events and atherosclerosis, manifested as coronary heart disease, stroke or peripheral arterial disease. Dietary supplementation with B vitamins that lower tHcy concentrations was expected to reduce cardiovascular disease (CVD) risk. However, recent metaanalyses of prospective observational studies and randomized controlled trials failed to show a role of tHcy in the pathogenesis of vascular disease or a benefit of B vitamins in CVD events. This review analyzes recent data on the potential of tHcy to cause health problems (if any) and the role of vitamin B supplementation in preventing them.